Catalysts
In recent years, it has become widely recognized that ligands having C2 symmetry can be used with great effect in the design of catalysts for asymmetric synthesis. Several reviews have addressed the use of such catalysts in asymmetric carbenoid reactions. These include: Singh et al., “Catalytic Enantioselective Cyclopropanation of Olefins Using Carbenoid Chemistry,” Synthesis, 1997:137–149 and Doyle, Chiral catalysts for Enantioselective Carbenoid Cyclopropanation Reactions,” Recl. Trav. Chim. Pays-Bas, 110:305–316 (1991). The use of these catalysts in asymmetric transformations has also been reported in Pfaltz, “Chiral Semicorrins and Related Nitrogen Heterocycles as Ligands in Asymmetric Catalysts,” Acc. Chem. Res., 26:339–345 (1993); Noyori, Asymmetric Catalysis in Organic Synthesis, New York: John Wiley & Sons, Inc., pp. 16–95 (1994); Evans et al., “Bis(oxazoline)-copper Complexes as Chiral Catalysts for the Asymmetric Aziridination of Olefins,” J. Am. Chem. Soc., 115:3328–3329 (1993); Li et al., “Asymmetric Alkene Aziridination With Readily Available Chiral Diimine-based Catalysts,” J. Am. Chem. Soc., 115:5326–5327 (1993); Nishikori et al., “Catalytic and Highly Enantioselective Aziridination of Styrene Derivatives,” Tetrahedron Lett., 37:9245–9248 (1996); Nicholas et al., “On the Mechanism of Alyllic Amination Catalyzed by Iron Salts,” J. Am. Chem. Soc., 119:3302–3310 (1997); Johnson et al., “Catalytic Asymmetric Epoxidation of Allylic Alcohols,” in Ojima, ed., Catalytic Asymmetric Synthesis, New York: VCH Publishers, Inc., pp. 103–158 (1993); and Jacobsen, “Asymmetric Catalytic Epoxidation of Unfunctionalized Olefins,” in Ojima, ed., Catalytic Asymmetric Synthesis, New York: VCH Publishers, Inc., pp. 159–202 (1993). The C2 symmetry of a complex cuts in half the number of possible arrangements that are available for the reacting substrate or substrates. Consequently, it becomes much easier to design a catalyst with well-defined chiral influence to effect high asymmetric induction of the reaction in question. A natural extension for chiral catalyst design would be to move from complexes having C2 symmetry to complexes having D2 symmetry. Catalysts having D2 symmetry would cut to a quarter the number of possible arrangements that are available for the reacting substrate or substrates and, thus, would have the potential of being very reliable chiral catalysts.
Even though the concept of using catalysts having D2 symmetry is a very attractive proposition, the practical outcome of trying to develop such catalysts has not had much success. The general strategy, such as that described in Maxwell et al., “Shape-selective and Asymmetric Cyclopropanation of Alkenes Catalyzed by Rhodium Porphyrins,” Organometallics, 11:645–652 (1992) (“Maxwell”), Morice et al., “Oxidation and Chiral Recognition of Amino Esters by Dioxoruthenium(VI) Porphyrins: Synthesis of a New Imino Ester Ru(II) Complexes,” Tetrahedron Lett., 37:6701–6704 (1996), and Halterman et al., “Synthesis of D2-symmetric Benzaldehydes and Achiral Arylsipyrromethanes,” Tetrahedron Lett., 37:6291–6294 (1996), has been to develop very elaborate D2 ligands built around a porphyrin core. However, the synthetic procedures for these ligands are long and give poor yields, and the resulting chiral catalysts perform only with moderate asymmetric induction. Maxwell suggests that one problem with these porphyrin complexes is that the chiral influence is too far removed from the metal center to be very effective in asymmetric induction.
In view of the unrealized promise of catalysts having D2 symmetry, there is a need for catalysts having D2 symmetry which are easily to produce and which have high asymmetric inductive effects. The present invention, in part, is directed to meeting this need.
Synthesis of Gem-Diarylalkyl Derivatives
The gem-diarylalkyl group is present in a number of important pharmaceuticals, such as tolterodine, CDP-840, and nomifensine, and sertraline. Consequently, a number of reports have recently appeared describing methods for the asymmetric synthesis of gem-diarylalkyl derivatives. These include: Frey et al., J. Org. Chem., 63:3120–3124 (1998) (“Frey”); Andersson et al., J. Org. Chem., 63:8067–8070 (1998) (“Andersson”); Houpis et al., Tetrahedron Lett., 38:7131–7134 (1997) (“Houpis”); Christenson et al., Tetrahedron, 47:4739–4752 (1991) (“Christenson”); Alexakis et al., Tetrahedron Lett., 29:4411–4414 (1988) (“Alexakis”); and Corey et al., Tetrahedron Lett., 35:5373–5376 (1994) (“Corey”). Particularly effective have been the asymmetric conjugate addition of organometallic reagents to cinnamates, decribed in Frey, Andersson, Houpis, Christenson, and Alexakis, and the aryl cuprate addition to enantiomerically pure dimethyl 2-phenylcyclopropane-1,1-dicarboxylate, described in Corey. However, these reaction schemes involve multiple steps with poor overall yields and inconsistent chiral purity.
Accordingly, a need continues to exist for methods for preparing asymmetric gem-diarylalkyl derivatives. The present invention, in part, is directed to meeting this need.
Formation of Carbon-Carbon Bonds
The aldol reaction is a central transformation in organic synthesis. See, for example, Heathcock in Morrison, ed., Asymmetric Synthesis, San Diego: Academic Press, Vol. 3, Chapter 2 (1984) (“Heathcock”). Not only is the reaction a powerful carbon-carbon bond forming process, but, also, Heathcock reports that the reaction can be made highly diastereoselective by using enolates of defined geometry. Furthermore, high enantioselectivity can be achieved by using chiral auxiliaries (Heathcock) or by using chiral catalysts. The use of chiral catalysts in enantioselective aldol reactions has been recently reviewed in Nelson, “Catalyzed Enantioselective Aldol Additions of Latent Enolate Equivalents,” Tetrahedron-Asymmetry, 9:357–389 (1998). Of particular interest are aldol reactions between enolates of arylacetates and aldehydes. For example, Evans et al., “C-2-symmetric Copper(II) Complexes as Chiral Lewis Acids. Scope and Mechanism of the Catalytic Enantioselective Aldol Additions of Enolsilanes to Pyruvate Salts,” J. Am. Chem. Soc., 121:669–699 (1999), recently reported a reaction between a silylketene acetal of phenylacetate and benzyloxyacetaldehyde using a Cu(II) bisoxazoline complex. The reaction resulted in low enantioselectivity (about 9%) and no diastereoselectivity. However, better asymmetric induction has been achieved in such aldol reactions by using chiral enolates (Lutzen et al., “D-xylose Derived Oxazolidin-2-ones as Chiral Auxiliaries in Stereoselective Aldol Reactions,” Tetrahedron-Asymmetry. 8:1193–1206 (1997)). However, processes of this type occurring in high yields and with good diastereoselectivity and enantioselectivity has not been reported.
Accordingly, a need continues to exist for methods for forming carbon-carbon bonds with good diastereoselectivity and enantioselectivity. The present invention, in part, is directed to meeting this need.
RITALIN™ and its Congeners
Attention Deficit Disorder (“ADD”) is the most commonly diagnosed illness in children. Symptoms of ADD include distractibility and impulsivity. A related disorder, termed Attention Deficit Hyperactivity Disorder (“ADHD”), is further characterized by increased symptoms of hyperactivity in patients. Racemic methylphenidate (e.g., RITALIN™) is a mild central nervous system stimulant, with pharmacological activity qualitatively similar to amphetamines, and has been the drug of choice for symptomatic treatment of ADD in children. Current administration of racemic methylphenidate, however, results in notable side effects, such as anorexia, weight loss, insomnia, dizziness, and dysphoria. Additionally, racemic methylphenidate, which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation and, thus, carries a high potential for substance abuse in patients.
At least 70% individuals who are infected with the Human Immunodeficiency Virus (“HIV”) who have developed Acquired Immunodeficiency Syndrome (“AIDS”) eventually manifest cognitive defects, and many display signs and symptoms of dementia. Complaints of forgetfulness, loss of concentration, fatigue, depression, loss of attentiveness, mood swings, personality change, and thought disturbance are common in patients with HIV disease. Racemic methylphenidate has been used to treat cognitive decline in AIDS patients. As described above, racemic methylphenidate, which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for drug abuse in AIDS patients.
Glutathione is an important antioxidative agent that protects the body against electrophilic reactive compounds and intracellular oxidants. It has been postulated that HIV-AIDS patients suffer from drug hypersensitivity due to drug overload and an acquired glutathione deficiency. Patients with HIV infection have demonstrated a reduced concentration of glutathione in plasma, cells, and broncho-alveolar lavage fluid. Clinical data suggest that HIV-seropositive individuals display adverse reactions to the simultaneous administration of several otherwise therapeutic drugs. It is therefore desirable to provide for the administration of methylphenidate in reduced dosages among patients with drug hypersensitivity due to HIV infection.
Methylphenidate possesses two centers of chirality and thus can exist as four separate stereoisomers. Diastereomers are known in the art to possess differing physical properties, such as melting point and boiling point. For example, while the threo-racemate of methylphenidate produces the desired effect on the cental nervous system, the erythro-racemate contributes to hypertensive side-effects and exhibits lethality in rats.
Additional studies in animals, children and adults have demonstrated pharmacological activity in the d-threo isomer of methylphenidate (2R:2′R). Although the role of the l-threo isomer in toxicity or adverse side effects has not been thoroughly examined, the potential for isomer ballast in methylphenidate is of concern for many patients, particularly those drug hypersensitive patients described above.
Although l-threo-methylphenidate is rapidly and stereo-selectively metabolized upon oral administration, intravenous administration or inhalation results in high l-threo-methylphenidate serum levels. Intravenous administration and inhalation are the methods of choice by drug abusers of current methylphenidate formulations, and it has been postulated that the euphoric effect produced by current formulations of methylphenidate is due to the action of the l-threo-methylphenidate.
Accordingly, it has been suggested that the use of the d-threo isomer (2R:2′R) of methylphenidate which is substantially free of the l-threo isomer produces high methylphenidate activity levels and simultaneously reduces methylphenidate's euphoric effect and the potential for abuse among patients.
Methods for synthesizing d-threo methylphenidate have been reported. However, these methods involve long, complicated syntheses, have poor overall yields, and require at least some separation of mixtures of enantiomers and/or diastereomers.
In view of the advantages of pure d-threo methylphenidate and the deficiency in the art of methods for making this compound and its congeners, a need exists for an improved synthetic method for making pure d-threo methylphenidate and its congeners. The present invention, in part, is directed to meeting this need.